Spray compositions for treatment of obstructive disorders of the respiratory tract and methods therefor

ABSTRACT

Inhalation spray compositions for the treatment of obstructive disorders of the respiratory tract, comprising as an active ingredient a physiologically compatible quaternary salt of N-isopropyl-N-methyl-nortropine tropic acid ester, optionally in combination with a mucolytic and/or a bronchospasmolytic.

United States Patent Zeile et al.

[151 3,681,500 [451 Aug. 1,1972

[54] SPRAY COMPOSITIONS FOR TREATMENT OF OBSTRUCTIVE DISORDERS OF THERESPIRATORY TRACT AND METHODS THEREFOR [72] Inventors: Karl Zeile;Werner Schulz; Rolf Banholzer; Helmut Wick, all of Ingelheim am Rhein,Germany [73] Assignee: Boehringer Ingelheim GmbH, Inge]- heim am Rhine,Germany 22 Filed: Dec. 3, 1970 21 App1.No.: 94,951

[30] Foreign Application Priority Data [56] References Cited UNITEDSTATES PATENTS 3,505,337 4/1970 Zeile et a1. ..260/292 FOREIGN PATENTSOR APPLICATIONS 708,644 12/1967 Belgium 24M 11/1960 France PrimaryExaminerStan1ey J. Friedman Attorney-Hammond & Littell [5 7] ABSTRACTInhalation spray compositions for the treatment of obstructive disordersof the respiratory tract, comprising as an active ingredient aphysiologically compatible quaternary salt ofN-isopropyl-N-methyl-nortropine tropic acid ester, optionally incombination with a mucolytic and/or a bronchospasmolytic.

14 Claims, No Drawings SPRAY COMPOSITIONS FOR TREATMENT OF OBSTRUCTIVEDISORDERS OF THE RESPIRATORY TRACT AND METHODS TIEREFOR This inventionrelates to inhalation spray compositions for the treatment ofobstructive disorders of the respiratory tract, comprising as an activeingredient a physiologically acceptable quaternary salt of N-isopropyl-N-methyl-nortropine tropic acid ester.

Tl-IE PRIOR ART Quaternary salts of N-isopropyl-N-methyl-nortropinetropic acid ester, their preparation and their use as secretolytics andspasmolytics by the oral, rectal and injection route of administrationare described in US. Pat. No. 3,505,337, issued Apr. 7, 1970.

THE INVENTION We have discovered that physiologically acceptablequaternary salts of N-isopropyl-N-methyl-nortropine tropic acid ester,and especially N-isopropylnoratropinium methobromide, are very effectivein reducing the air flow resistance in the respiratory tract whenadministered per inhalationem, and are therefore useful for thetreatment of obstructive disorders of the respiratory tract, such asasthma, in warm-blooded animals including humans.

Thus, the present invention relates to nebulizable inhalation spraycompositions consisting essentially of an inert, pharmaceuticallyacceptable liquid carrier and, as the active ingredient, from 0.001 to3.0 percent, preferably 0.005 to 1.5 percent, based on the total weightof the composition, of a pharmaceutically acceptable quaternary salt ofN-isopropyl-N-nortropine tropic acid ester and optionally also anefiective amount of a mucolytic and/or of a broncho-spasmolytic; as wellas to the method of treating obstructive disorders of the respiratorytract in warm-blooded animals and humans by administering saidcompositions per inhalationem.

Examples of pharmaceutically acceptable quaternary salts ofN-isopropyl-N-methyl-nortropine tropic acid ester are those whose anionis the anion of hydrobromic, nitric or methanesulfonic acid; however,particularly preferred is N-isopropyl-N-methylnoratropiniummethobromide.

Examples of mucolytic agents suitable for optional incorporation intothe inhalation spray compositions according to the present invention arethe known cysteine derivatives N-acetyl-L(+)-cysteine andcysteine-N-acetic acid hydrochloride.

Examples of bronchial antispasmodic agents suitable for optionalincorporation into the inhalation spray compositions of the presentinvention are l-(3',5'- dihydroxy-phenyl 1 -hydroxy-2-[ l'-(p-hydroxy-phenyl)-isopropyl-amino]-ethane hydrobromide and N-cyclohexyl-N-methyl-2-(2-amino-3,5-dibromo)- benzylammonium chloride.

The inhalation spray compositions pursuant to the present invention areprepared by dissolving the active ingredient or ingredients in asuitable pharmaceutically acceptable inert, nebulizable liquid,preferably water; the resulting solution is then filled into aconventional atomizing device, such as an inhaler, provided with ametering spray valve. Another way of preparing the inhalation spraycompositions is to dissolve or suspend the active ingredient oringredients, if necessary with the aid of a suitable conventionalsolution promoter or auxiliary suspension agent,in a conventional,pharmaceutically acceptable propellant gas which has been liquefied bycompression or deep cooling, and filling the resulting composition intoa conventional aerosol container provided with a metering aerosol sprayvalve.

In either case, the inhalation spray produced thereby is an effectivecomposition for the treatment of obstructive disorders of therespiratory tract per inhalationem. In comparison to atropine, onlyone-fortieth of the amount of the active ingredient according to thepresent invention is required to achieve the same effect 5 as withatropine, and the compositions of the instant invention have the furtheradvantage that they do not produce the undesirable side effects commonlyobserved with inhalation sprays comprising atropine as an activeingredient.

The efiectiveness of N-isopropyl-noratropinium methobromide as an agentfor reducing the air flow resistance caused by obstructive disorders,such as asthma, was ascertained in a series of clinical tests on adultpatients. The afilicted test subjects were made to inhale for one minutea mist produced by nebulizing an aqueous 0.025 percent and 0.0125percent solution, respectively, of N-isopropyl-noratropiniummethobromide with the aid of a conventional inhaler having an airthrough-put rate of 6.5 liters/minute. The air flow resistance in therespiratory tract was measured just before commencement of theinhalation and then 5, 30,

60, and minutes after the inhalation. The following results wereobtained:

TABLE Concentration of No. of Average value of air flow The followingexamples illustrate a few inhalation spray compositions pursuant to thepresent invention, and will enable others skilled in the art tounderstand the invention more completely. The percentages are percent byweight.

EXAMPLE 1 Aerosol The spray composition was compounded from thefollowing ingredients:

N-lsopropyl-noratropinium methobromide 0.007 1.43% Sorbitan trioleate(surfactant) 0.500 2.00% Propellant mixture consisting ofmonofluorotrichloromethane and difluorodichloromethane (40 60) q.s.ad100% Preparation The noratropinium compound and the surfactant weresuspended in the propellant mixture which had previously been liquefiedby compression or deep cooling, and the suspension was filled into anaerosol container provided with a metering valve which dispensed anaerosol containing from 5 to 1,000 of the noratropinium compound witheach actuation of the valve. When the amount of aerosol thus expelledwas inhaled by an adult person afflicted with an obstructive disorder ofthe respiratory tract, such as asthma, the air flow resistance in therespiratory tract was markedly decreased and free breathing restoredafter a few minutes.

EXAMPLE 2 Aerosol With Combination of Bronchospasmolytics The spraycomposition was compounded from the following ingredients:

q.s. ad 100% Preparation The active ingredients and the surfactant weresuspended in the propellant mixture which had previously been liquefiedby compression or deep cooling, and the suspension was filled into anaerosol container provided with a metering valve which dispensed anaerosol containing from 5 to 1,000 7 of the noratropinium compound andfrom 50 2007 of the bronchospasmolytic with each actuation of the valve.When the amount of aerosol thus expelled was inhaled by an adult personafflicted with an obstructive disorder of the respiratory tract, such asasthma, the air flow resistance in the respiratory tract was markedlydecreased and free breathing restored after a few minutes.

EXAMPLE 3 lnhalation Spray With Bronchospasmolytic The spray compositionwas compounded from the following ingredients:

N -Isopropyl-noratropinium methobromide Aqueous solution ofN-cyclohexyl-N-methyl-2-(2-amino-3,5- dibromo)benzylammonium chloride (2mgm/ml) q.s.ad [00% disorder of the respiratory tract, such as asthma,the air flow resistance in the respiratory tract was markedly decreasedand free breathing restored after a few minutes, and an effectivebrochospasmolytic action was produced.

EXAMPLE 4 N-lsopropyl-noratropinium methobromide Aqueous solution ofN-acetyl- L(+)-cysteine or cysteine-N- acetic acid hydrochloride sq.s.ad 100% EXAMPLE 5 lnhalation Spray The spray composition wascompounded from the following ingredients:

N-lsopropyl-noratropinium methobromide 0.005 0.4% Phosphate buffersolution pHS (aqueous) q.s.ad l00% Preparation The noratropiniumcompound was dissolved in the aqueous bufier solution, and the resultingsolution was filled into a conventional atomizing inhaler provided witha spray valve and an actuator piston which expelled a spray containingfrom 5 to 1,000 of the noratropinium compound with each stroke of thepiston. When the spray thus expelled was inhaled by an adult personafflicted with an obstructive disorder of the respiratory tract, such asasthma, the air flow resistance in the respiratory tract was markedlydecreased and free breathing restored after a few minutes.

While the present invention has been illustrated with the aid of certainspecific embodiments thereof, it will be readily apparent to othersskilled in the art that the invention is not limited to these particularembodiments, and that various changes and modifications may be madewithout departing from the spirit of the invention or the scope of theappended claims.

We claim:

1. The method of reducing the air flow resistance in the respiratorytract of a human patent afflicted with an asthmatic disorder of therespiratory tract, which comprises administering to said patient perinhalationem from 5 to 1,000 7 of a pharmaceutically acceptable 55quaternary atropinium salt of the formula 1,0(10y of the noratropiniumcompound with each 6 stroke of the piston. When the spray thus expelledwas inhaled by an adult person afilicted with an obstructive wherein Xis the anion of an acid.

2. The method according to claim 8, where X is the anion of hydrobromic,nitric or methanesulfonic acid.

3. The method according to claim 8, where X is the anion of hydrobromicacid.

4. The method according to claim 8, which comprises simultaneouslyadministering to said patient per inhalationem and effectivebronchospasmolytic amount of a bronchial antispasmodic selected from thegroup consisting of 1-(3,5-dihydroxy-phenyl)-lhydroxy-2-[ l"-(p-hydroxy-phenyl)-isopropyl-amino]- ethane hydrobromide andN-cyclohexyl-N-methyl-Z- (2-amino-3 ,S-dibromo )-benzyla.mmoniumchloride.

5. The method according to claim 8, which comprises simultaneouslyadministering to said patient per inhalationem an effective mucolyticamount of a compound selected from the group consisting of N-acetyl-L(+)-cysteine and cysteine-N-acetic acid hydrochloride.

6. A pharmaceutical inhalation spray composition for treating asthmaticdisorders of the respiratory tract, consisting of 0.007 to 1.0 percentweight, based on the total weight of said composition, of apharmaceutically acceptable quaternary atropinium salt of the formula HCH CH:

total weight of said composition, of a pharmaceutically acceptablequaternary atropinium salt of the formula wherein X is the anion of anacid, and the balance an aqueous solution of 0.2 mgm/ml of a mucolyticselected from the group consisting of N-acetyl-L(+)- cysteine andcysteine-N-acetic acid hydrochloride.

9. A composition according to claim 8, wherein said atropinium salt isN-isopropyl-noratorpinium methobromide.

10. A pharmaceutical inhalation spray composition for treating asthmaticdisorders of the respiratory tract, consisting essentially of aneffective amount of a pharmaceutically acceptable quaternary atropiniumsalt of the formula mg i UNITED shirts PATENT OFFICE CERTIFICATE OFCORRECTION Patent No. 3,681,500 Dated August 1, 1972 Inventor) KARLZEILE, WERNER SCHULZ, ROLF BANHOLZER and HELMUT WICK It is certifiedthat error appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

" 001. 3, line 6: insert /a after "1,000"

Cols. and 5:' Claims 2, 3, 4 andf5, lane 1 of each, i change "claim 8"to "slain l--. D Col; 5, line 3 9; insert --by-- before "weight" C01. 6,line 40: correct the spelling of "dihydroxy";

" 6, line +1: correct the spelling of "ethane";

'1' 6, line 37-: delete "-d1pydroi hen 1)-".

Signed and sealed this 15th day of May 1973.

(SEAL) Attest:

M.FLET( $H ER JR. ROBERT GOTISCHALK. es lng offlcer CommissionerofPatents UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE EXTENDINGPATENT TERM UNDER 35 U.S.C. 156

Patent No. 3,681 ,500

Dated August 1 1972 Inventor(s) Karl Zeile, et al Patent OwnerBoehringer Ingelheim International GmbH This is to certify that therehas been presented to the COMMISSIONER OF PATENTS AND TRADEMARKS anapplication under 35 U.S.C. 156 for an extension of the patent term.Since it appears that the requirements of law have been met, thiscertificate extends the term of the patent for the period of 2 YEARSwith all rights pertaining thereto as provided by 35 USC 156 (b) I havecaused the seal of the Patent and Trademark Office to be affixedAssistant Secretary and Commissioner of Patents and Trademarks thisTwenty-second day of March 1988.

2. The method according to claim 8, where X is the anion of hydrobromic,nitric or methanesulfonic acid.
 3. The method according to claim 8,where X is the anion of hydrobromic acid.
 4. The method according toclaim 8, which comprises simultaneously administering to said patientper inhalationem and effective bronchospasmolytic amount of a bronchialantispasmodic selected from the group consisting of1-(3'',5''-dihydroxy-phenyl)-1-hydroxy-2-(1''''-(p-hydroxy-phenyl)-isopropyl-amino)-ethane hydrobromide andN-cyclohexyl-N-methyl-2-(2-amino-3,5-dibromo)-benzylammonium chloride.5. The method according to claim 8, which comprises simultaneouslyadministering to said patient per inhalationem an effective mucolyticamount of a compound selected from the group consisting ofN-acetyl-L(+)-cysteine and cysteine-N-acetic acid hydrochloride.
 6. Apharmaceutical inhalation spray composition for treating asthmaticdisorders of the respiratory tract, consisting of 0.007 to 1.0 percentweight, based on the total weight of said composition, of apharmaceutically acceptable quaternary atropinium salt of the formula 7.A composition according to claim 6, wherein said atropinium salt isN-isopropyl-noratropinium methobromide.
 8. A pharmaceutical inhalationspray composition for treating asthmatic disorders of the respiratorytract, consisting of 0.007 to 1.0 percent weight, based on the totalweight of said composition, of a pharmaceutically acceptable quaternaryatropinium salt of the formula
 9. A composition according to claim 8,wherein said atropinium salt is N-isopropyl-noratorpinium methobromide.10. A pharmaceutical inhalation spray composition for treating asthmaticdisorders of the respiratory tract, consisting essentially of aneffective amount of a pharmaceutically acceptable quaternary atropiniumsalt of the formula
 11. A composition according to claim 10, whereinsaid non-aqueous liquid carrier is a liquified mixture ofmonofluoro-trichloro-methane and difluoro-dichloromethane.
 12. Acomposition according to claim 10, wherein said atropinium salt isN-isopropyl-noratropinium methobromide.
 13. A composition according toclaim 10, which additionally comprises up to 2 percent by weight ofsorbitan tri-oleate. -dihydroxy-phenyl)-
 14. A composition according toclaim 13, which additionally comprises an effective bronchospasmolyticamount of1-(3'',5''-dhydroxy-phenyl)-1-hydroxy-2-(1''''-(p-hydroxy-phenyl)-isopropyl-amino)-ethan hydrobromide.